Dibenzoxazepine N-carboxylic acid hydrazides and derivatives

ABSTRACT

Derivatives of the dibenzoxazepine N-carboxylic acid hydrazides are acylated to yield N,N&#39;&#39;-diacyl hydrazines which are useful pharmacological agents as is evidenced by their anti-arrhythmic, anti-inflammatory, anti-diarrheal, prostaglandin antagonist and 5-hydroxytryptamine antagonist activity.

Umted States Patent 1191 [111 3, Mueller 5] Nov. 4, 1975 [54]DIBENZOXAZEPINE N-CARBOXYLIC ACID 3,624,104 10/1969 Cusic et a]. 260/333HYDRAZIDES AND DERIVATIVES 75 Inventor: Richard A. Mueller, Glencoe,111. OTHER PUBPICATIONS AssigneeI Searle & C Chicago, William E. Coyneet al., J. Med. Chem, 11 (6) 22 Filed: Aug. 12, 1974 PP- 1158-1160- [21]Appl. N0.: 496,692

Prima ExaminerNorma S. Milestone 1 t d U S Apphcatlon Data Attorney,Agent, or Firm-Elliot N. Schubert; John J. [63] Continuation-impart ofSer. Nos. 127,360, March 23, McDonnell 1971, abandoned, and Ser. No.329,407, Feb. 5, 1973, abandoned.

[30] Foreign Application Priority Data [57] ABSTRACT Mar. 22, 1972Australia 40272/72 Derivatives of the dibenzoxazepine N-carboxylic acid[52] US. Cl 260/333; 424/244; 260/240 K h d id are l t d t yieldN,N-diacyl hydra- [51] Int. Cl. C07D 267/20 Zines hi h are ful harmaological agents as is ev- [58] Fleld 0f Search 260/333 idenced by theiranti-arrhythmic anti-inflammatory,

anti-diarrheal, prostaglandin antagonist and S-hydrox- References Cltedytryptamine antagonist activity.

UNITED STATES PATENTS 3,534,019 10/1970 Coyne et al 260/333 10 Claims,N0 Drawings DIBENZOXAZEPINE N-CARBOXYLIC ACID HYDRAZIDES AND DERIVATIVESThis application is a continuation-in-part of my copending applicationsSer. No. 127,360, filed Mar. 23, 1971, now abandoned, and Ser. No.329,407, filed Feb. 5, 1973 and now abandoned. I

This invention is concerned generally with derivatives of thedibenzoxazepine N-carboxylic acid hydrazides and more specifically withcompounds of the following general formula wherein Y and Y are hydrogen,halogen, methyl or trifluoromethyl, X is carbonyl or sulfonyl and when Xis carbonyl, R is hydrogen, perfluoroalkyl, carboxyalkenyl, alkenyl,aryloxyalkyl, carboxyalkyl, haloalkyl, haloaryloxyalkyl, aralkenyl orcyanoalkyl, and when X is sulfonyl, R is alkyl, haloalkyl, aryl oraralkyl. The alkyl radicals intended contain 1-12 carbon atoms and areillustrated bymethyl, ethyl, propyl, butyl, and the correspondingbranched-chain isomers. The halo radicals intended are chlorine, iodine,bromine and fluorine. The alkenyl radicals comprehended contain 1-12carbon atoms and are typified by vinyl, propenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl andthe branched-chain isomers thereof. Typical of the aryl radicals denotedin the foregoing formula are phenyl, tolyl and xylyl, while the aralkylradicals are illustrated by benzyl, phenethyl, etc., and the aralkenylradicals by phenalkenyl groups such as cinnamyl, phenallyl, etc.

A most preferred method of producing the compounds of the presentinvention involves the use of optionally substituted dibenzoxazepineN-carboxylic acid hydrazides as starting materials. The preparation ofthese compounds is disclosed in U.S. Pat. No. 3,534,019.

Acylation of the aforementioned hydrazides with the appropriateacylating agent in an inert medium affords the desired N,N'-diacylhydrazines. When a cyclic acid anhydride is employed as the acylatingagent, the carboxyalkanoyl or carboxyalkenoyl hydrazines are obtained.The instant sulfonylhydrazides are conveniently prepared by using, asthe acylating agent, the appropriate sulfonyl halides. When acylation isaccomplished with the use of a halo, phenoxy, or halophenoxy substitutedalkanoyl halide, the corresponding substituted hydrazines arerespectively produced.

The acid chlorides and acid anhydrides are most preferred acylatingagents. Preferred bases are triethylamine, collidine, lutedine,potassium carbonate, sodium bicarbonate and sodium carbonate, andconvenient solvents are benzene-methylene chloride, acetonitrile andbenzene. A

Typical of the reactions providing the carboxyalkanoyl hydrazinederivatives is that of 8-chloro-l0,1 l-

dihydrodibenz[b,f][ 1,4]oxazepine- 1 O-carboxylic acid hydrazide withglutaric anhydride thus affording l-(4- carboxybutyryl)-2-(8-chloro-10,1l-dihydrodibenz[ b,f][ 1 ,4]-oxazepinelO-carbonyl )hydrazine. In asimilar manner, when 8-chlor0-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide is reacted with5-chloropentanoyl chloride, phenoxyacetyl chloride, orp-chlorophenoxyacetyl chloride, 1-( 5-chloropentanoyl )-2-( S-chloro-10,1 1- dihydrodibenz[b,f][ 1,4]oxazepinel O-carbonyl )hydrazine,1-phenoxyacetyl-2-( 8-chloro-10, 1 l-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, and1r(p-chlorophenoxyacetyl)-2-(8-chloro-10,1 l-dihydrodibenz[b,f][1,4]oxazepinelO-carbonyl )hydrazine, respectively, are obtained.

Also, the compounds of the present invention may be prepared by treatingthe dibenzoxazepine carbonyl chloride in a basic medium with theappropriate acyl hydrazide. This method is particularly convenient whenthe alkanoyl chlorides are difficult to prepare.

The novel compounds of this invention are valuable pharmacologicalagents. They are active prostaglandin and S-hydroxytryptamineantagonists. In addition, they exhibit anti-arrhythmic,anti-inflammatory and antidiarrheal activity. They possess greaterpotency than previously disclosed compounds and also exhibit minimalundesirable effects upon the central nervous system.

The prostaglandin and S-hydroxytryptamine antagonist activity isdemonstrated in the following procedure which is substantially the sameas that described by J. H. Sanner, Arch. int. Pharmac0dyn., 180 (1),, 46(1969):

Female albino guinea pigs weighing 200-500 g. are sacrificed by cervicaldislocation and the ileum is quickly removed and placed in modifiedTyrode solution containing one-half the usual amount of magnesium ions.Segments of ileum, about 2 centimeters long are cut and mounted in a 2or 4 ml. tissue bath containing the modified Tyrode solution. Thesolution is maintained at 37 and bubbled with a gaseous mixture of 95%oxygen and 5% carbon dioxide. Contractions are detected isotonically.Approximately equal submaximal contractions are obtained in preliminarytrials by adjusting the doses of prostaglandin E (PGE and 5-hydroxytryptamine added to the bath. Two control contractions areobtained at 3.5 minute intervals. A solution or suspension of the testcompound in the bath ing solution is then substituted for the originalmodified Tyrode solution. The test suspension is kept in constantcontact with the tissue for the remainder of the experiment except forbrief periods to drain the bath in preparation for rinsing with freshtest suspension. Three more contractions are elicited to each agonist inthe presence of the test compound without interrupting the timesequence. The last two sets of treated responses are compared with thetwo sets of control responses. The first set of treated responses is notused for comparisons, being used only to maintain the timed sequence ofinjections during the period allowed for the tissue to becomeequilibrated with the antagonist. A compound is rated active if the meanof contractions produced by any agonist is reduced or more by the testcompound.

The anti-inflammatory properties of the instant compounds isdemonstrated by their activity in an assay adapted from that describedby Tonelli et al., Endocrinology, 77, 625 (1965) and detailed asfollows:

0.1 Cubic centimeter of a phlogistic vehicle consisting of.4 parts ofpyridine, 1 part of distilled water, 5 parts of diethyl ether and 10parts of 2% Croton oil in ether (v/v) is applied topically to the rightear of each of a group of 8-10 rats, while the contralateral left earremains untreated and serves as the control. For the determination ofactivity of the test compound a similar group of animals is treated withthe same volume of the phlogistic vehicle containing 400 mcg. of thecompound. In addition, a third group of animals is treated in the samemanner with the same volume of the phlogistic vehicle containing 80 mcg.of a standard topical anti-inflammatory agent (hydrocortisone).

Six hours after treatment the animals are lightly etherized and bothears are removed by means of a scissors, using anatomical structures ofthe ears as the line of demarcation. The ears are weighed individuallyand the percent increase in weight of the inflamed car as compared tothe untreated contralateral ear is determined. The percent tissue in earweight of the compound treated group is then compared statistically byWilcoxon Rank Sum Analysis with the percent increase in ear weight ofthe control group which received the phlogistic vehicle alone.

The anti-diarrheal properties of the compounds of this invention areapparent from their activity in the following assay procedure.

To groups of 10 Charles River male mice weighing 3040 g. is administeredintraperitoneally a selected dose of the test compound suspended in anaqueous medium containing 0.1% of polysorbate 80 (polyoxyethylenesorbitan mono-oleate). A constant volume of 0.1 ml./1O g. body weight ofthe suspension is used for each animal.

Fifteen minutes after administration of the test compound, the mice areinjected intraperitoneally with 50 pg/kg. body weight of prostaglandin Ethe dose previously demonstrated to produce diarrhea in more than 95% ofcontrol animals. Thereafter, each mouse is placed on a disc of filterpaper in an individual glass cylinder and observed for a period ofminutes for the presence or absence of diarrhea. The compound is testedat a variety of dosage levels until at least one dose results inprotection of more than 50% of the mice and one dose in less than 50% ofthe mice. The protective dose 50 (pD is calculated by the method of D.J. Finney, Statistical Method in Biological Assay, Chapter 17, HafnerPublishing Co., New York, 1964, using the proportion of mice protectedby each dose of compound.

The following examples will further illustrate the present invention.They should not be construed as limiting the invention either in spiritor in scope as modifications both in materials and methods will beapparent to those skilled in the art. In these examples temperatures areindicated in degrees Centigrade and quantities of materials in parts byweight unless parts by volume is specifically expressed.

EXAMPLE 1 To 1 part of 8-chloro-10,1 l-dihydrodibenz[b,f][ 1 ,4]oxazepinel 0-carboxylic acid hydrazide dissolved in 50 parts by volumeof 1:1 benzene-methylene chloride solution, is added in one portion0.344 part of maleic anhydride. The reaction mixture is stirred at roomtemperature for 24 hours, and the solvent is evaporated to yield an oilwhich is crystallized from benzene-ethyl acetate solution.Recrystallization from ethyl acetate-cyclohexane-ethanol solution yields1-(3carboxypropenoyl)-2-(S-chloro-l0, l l-dihydrodibenz[b,f] 1,4loxazepine- 1 0-carbonyl)hydrazine,

4 melting at about 171l72. This compound can be represented by thefollowing structural formula EXAMPLE 2 When an equivalent quantity ofglutaric anhydride is substituted in the procedure of Example 1, thereis obtained l-(4-carboxyturyryl)-2-( 8-chloro- 1 0, 1l-dihydrodibenz[b,f][ l ,4]oxazepine- 10-carbonyl)hydrazine, melting atabout 173l76 with decomposition. This compound is structurallyrepresented by the following formula EXAMPLE 3 By substituting anequivalent quantity of succinic anhydride in the procedure of Example 1,there is produced l-(3-carboxypropionyl)-2-(8-chloro- 10, 1 1-dihydrodibenz[b,f][ 1 ,4]oxazepinel 0-carbonyl)hydrazine, melting atabout 177-l79 with decomposition. This compound is represented by thefollowing structural formula EXAMPLE 4 5 6 pound is represented by thefollowing structural for mula i cH -N F Cl CNHNH(l: (CH-J,)-I CI"-NHNH-lC'CH -O I0 EXAMPLE 8 O O When equivalent quantities of3-phenoxypropionyl chloride and sodium carbonate are substituted in theprocedure of Example 4, 1-(3-phenoxypropionyl)-2- 5 i (8-ChlOlO-l0,l

l enz[b,f][l,4]oxazepine-10-carbonyl)hydrazine is af- Upon substitutingequivalent quantltles of triethylf 1 amine and p-chlorophenoxyacetylchloride and otherwise following the procedure of Example 4, one obtainsEXAMPLE 9 -(P P y J y By substituting equivalent quantities of3-(p-chlorol fll l p y l y phenoxy)propionyl chloride and sodiumcarbonate and which melts at about 1380-1390 with decompositionotherwise following the procedure of Example 4, there and is representedby the following structural formula i i d 1 3 i 1 2 gchloro- 10, 1l-dihydrodibenz[b,f][ 1,4]oxazepine- 1 0-carbonyl)hydrazine.

EXAMPLE 6 EXAMPLE 10 By substituting equivalent quantities of SodlumSubstitution of equivalent quantities of 6-chlorohexbonate and chlonde mthe From 4 anoyl chloride and sodium carbonate in the procedure dure ofExample there lsproducfd 'l of Example 4 produces1-(6-chlorohexanoyl)-2-(8- ichloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-l0-enz[b,f][1,4]oxazep1ne-1O-carbonyl)hydrazme, WlllCh carbonynhydrazine'has a melting point at about 148-149 and is structurally represented bythe following formula EXAMPLE 11 When equivalent quantities ofn-butylsulfonyl chloride and sodium carbonate are substituted in theproce dure of Example 4, there is produced l-(n-butyl-sulfonyl)-2-(8-chloro- 10,1 1-dihyd1rodibenz[b,f][ 1,4]ox- Clazepine10-carbonyl)hydrazine melting at about H2 N l48l50.

To a solution containing 1.45 parts of 8-chloro- 10,1l-dihydrodibenz[b,f][ 1,4]oxazepine- 1 O-carboxylic acid hydrazidedissolved in. 50 parts by volume of EXAMPLE 7 benzene is addedsuccessively (1.7 part by volume of triethylamine and 0.81 part ofcinnamoyl chloride. The resulting reaction mixture is stirred at roomtempera- When 0116 Substitutes y J yture for about 48 hours, then iswashed successively drodibenz[b,f][1,4loxazepine-lo-carboxylic acidywith dilute hydrochloric acid, dilute aqueous sodium drazide, Sodiumcarbonate and 5-chloropentanoyl hydroxide, water and saturated aqueoussodium chlochloride in the procedure of Example there is P ride. Dryingover anhydrous sodium sulfate followed by c d p y y removal of thesolvent by distillation under reduced 10,1 l-dihydrodibpressure affordsa residue, which is purified by adsorp- 1. 1 p yh y This tion on asilicic acid chromatographic column and elu- Compohhd melts at about12150-12350 and is p tion with ethyl acetate-benzene mixtures. The 10%sented by the following structural formula ethyl acetate in benzeneeluate, upon removal of the ,zation from benzene,

solvents, affords 1-cinnamoy1-2-(8-chloro-10,1l-dihydrodibenz[ b,f][ 1,4]oxazepine- 1 -carbonyl)hydrazine.

EXAMPLE 13 The substitution of an equivalent quantity of crotonylchloride in the procedure of Example 12 affords, after chromatography ona silicic acid column as described in that Example,l-crotonyl-2-(8chloro-10,l l-dihydrodibenz[b,f][ 1,4]oxazepinel0-carbonyl)hydrazine, melting at about l051 When thatmaterial is dried under vacuum at approximately 100105, the pureproduct, melting at about 178182, is obtained.

EXAMPLE 14 To a solution containing 5 parts of 8chloro-10,1 1-dihydrodibenz[b,f][ l ,4]oxazepinel O-carbonyl chloride in 60 parts byvolume of acetonitrile is added successively 1.68 parts ofcyanoacetohydrazide and excess sodium bicarbonate. The resultingreaction mixture is stirred at room temperature for about 24 hours, thenis diluted with benzene and stirred for approximately 30 minutes longer.The resulting mixture is filtered and the filtrate is concentrated todryness under reduced pressure to afford the crystalline product.Purification by recrystallization from ethanol using decolorizingcarbon, affords pure 1-cyanoacetyl-2-(8-chloro-10,1 ldihydrodibenz[b,f][ 1,4]oxazepine- 1 O-carbonyl)hydrazine, melting at about 2082l0.

EXAMPLE 15 To a solution containing 2.9 parts of 8-chloro- 10,1 1-dihydrodibenz[b,f][ 1,4]oxazepinelO-carboxylic acid hydrazide dissolvedin 50 parts by volume of acetonitrile containing excess aqueouspotassium carbonate is added 0.95 parts of l-methyl-l-phenoxyacetylchloride and the resulting reaction mixture is stirred at roomtemperature for about 48 hours. The solvent is removed under reducedpressure and the resulting residue is purified by chromatography on asilica gel column followed by elution with hexane-benzene solutions. The10% hexane in benzene eluate affords 1-(1-methyll-phenoxyacety1)-2-(8chloro- 1 0 ,1 1 -dihydrodibenz[b ,f][1,4]oxazepine- 1 O-carbonyl )hydrazine, melting at 150153.

EXAMPLE 16 When an equivalent quantity of p-toluenesulfonyl chloride issubstituted in the procedure of Example 15, there is producedl-p-toluenesulfonyl-2-(8-chloro- 10,1 1-dihydrodibenz[ b,f][ 1 ,4]0xazepine- 1 O-carbonyl )hydrazine, which, after recrystallization frombenzene-cyclohexane, affords the pure product, melting withdecomposition at about 206209.

4 EXAMPLE 17 When an equivalent quantity of benzylsulfonyl chloride issubstituted in the procedure of Example 16 and the reaction is continuedfor approximately 48 hours at room temperature, there is produced, afterrecrystallipure 1-benzylsulfonyl-2-( 8- chloro-10,1l-dihydrodibenz[b,f][1,4]oxazepine-10- carbonyl )hydrazine, melting withdecomposition at about 1 l8 -l.

EXAMPLE 18 When equivalent quantities of methanesulfonyl chlo ssubstituted" in the procedure of Example 12, there is produced, afterrecrystallization from benzene, 1- methanesulfonyl-2-( 8-chloro- 10,1l-dihydrodibenz[ b,f][ 1,4]oxazepine-l0-carbonyl)hydrazine, melting withdecomposition at about 1081 10.

EXAMPLE 19 The substitution of an equivalent quantity of 3-chloropropylsulfonyl chloride in the procedure of Example 12 affords,after recrystallization from benzenecyclohexane, 1-(3-chloropropylsulfonyl)-2-( 8- chloro-10,1 l-dihydrodibenz[b,f][ 1,4]oxazepine- 10- carbonyl)hydrazine, melting with decomposition atabout 167170.

EXAMPLE 20 When an equivalent quantity of 4-chlorobutyryl chloride andalso an equivalent quantity of sodium carbonate, as the acid acceptor,are substituted in the procedure of Example 4, there is produced 1-(4-chlorobutyryl)-2-(8-chloro-l0,1.1-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, melting, after recrystallizationfrom either benzenecyclohexane or benzenehexane, at about 154156.

EXAMPLE 2 1 By substituting an equivalent quantityof 5-bromopentanoylchloride in the procedure of Example 20, there is produced1-(5-bromopentanoyl)-2-(8-chloro- 10, l l-dihydrodibenz[b,f][ 1,4]oxazepine10-carbonyl)hydrazine, melting at about 147149.

EXAMPLE 22 When an equivalent quantity of 5-chloro-3-methylpentanoylchloride and an equivalent quantity of potassium carbonate, as the acidacceptor, are substituted in the procedure of Example 18, there isobtained, after recrystallization from cyclohexane, 1-'( 5-chloro-3-methylpentanoyl)-2-(8-chloro-10,1 l-dihydrodibenz[ b,f][1,4]oxazepine-10-carbonyl)hydrazine, melting at about -128'. I

EXAMPLE 23 When the procedure of Example 12 is carried out, substitutingequivalent quantities of chloroacetic anhydride as the acylating agentand sodium bicarbonate as the acid acceptor, there is produced1-chloroacetyl-2- (8-chlorol 0,1 1-dihydrodibenz[b,f][ 1 ,4]oxazepine-10-carbonyl)hydrazine, melting at about 174l76.

EXAMPLE 24 tion is then filtered and the resultant layers separated.

The benzene layer is dried over anhydrous sodium sulfate and the solventremoved by distillation under reduced pressure. The resulting residualoil is purified by trituration with-hexane, followed byrecrystallization ..from benzene,.thus affording l-trifluoroacetyl-2-(8-ride and sodium carbonate, as the acid acceptor are chloro-10,1l-dihydrodibenz- [b,f][ 1 ,4]oxazepine-10- To a suspension of 2.88 partsof 8-chloro-10,1 l-dihydrodibenz[b,f][ 1 ,4]oxazepine-10-carboxylic acidhydrazide with 100 parts by volume of dry benzene is added about 1 partof formic acetic anhydride, prepared from 10.2 parts of acetic anhydrideand 4.6 parts of formic acid. The reaction mixture is stirred until noevidence of starting material is detected, at which time 100 parts ofwater is added with vigorous stirring. Stirring is continued for about 1hour, at the end of which time the mixture is filtered and the resultingproduct is dried to afford 1-formyl-2-(8-chloro-10,1l-dihydrodibenz[b,f][ l ,4]oxazepine-10-carbonyl)hydrazine, melting atabout 177181.

EXAMPLE 26 To a suspension of 2.88 parts of 8-chloro-10,ll-dihydrodibenz[b,f][ 1,4]oxazepine-10-carboxylic acid hydrazide in 100parts by volume of benzene is added 2.33 parts of perfluorobutyrylchloride, followed by about 1.5 parts of triethylamine. The reactionmixture is stirred at room temperature for about 48 hours and 100 partsof water is then added with vigorous stirring. The benzene layer isseparated, dried over anhydrous sodium sulfate and distilled to drynessunder reduced pressure, thus affording 1-perfluorobutyryl-2-( 8- chlorol0,1 1 -dihydrodibenz[b,f][ 1 ,4 ]oxazepine- 1 O-carbonyl )hydrazine,which compound is exemplified by the following structural formula F F FCNHNHC l l p ll l l 0 F F EXAMPLE 27 To a solution of 2.88 parts of8-chloro-10,1l-dihydrodibenz[b,f][ 1,4]oxazepine-lO-carboxylic acidhydrazide in 88 parts of benzene is added 4.32 parts by volume ofperfluorooctanoyl chloride and excess solid sodium carbonate. Themixture is stirred at room temperature for about 72 hours, then dilutedwith water and the organic layer is separated and dried over anhydroussodium sulfate. Distillation of the solvent under reduced pressureaffords the desired l-perfluorooctanoyl-2-( 8-chloro- 10,1l-dihydrodibenz[ b,f][ 1 ,4]oxazepine-10-carbonyl)hydrazine,characterized by the following formula.

What is claimed is: l. A compound of the formula Y (H -N IdINHNHCR 0wherein Y is selected from the group consisting of halogen andtrifiuoromethyl radicals, R is a radical selected from the groupconsisting of alkenyl, carboxyalkenyl, carboxyalkyl, cyanoalkyl,haloalkyl, phenoxyalkyl and halophenoxyalkyl, and the alkyl and alkenylradicals in each instance contain 1-12 carbon atoms.

2. As in claim 1, the compound which is 1-(3-carboxypropenoyl)-2-(8-ch1oro-10,1 l-dihydrodibenz[b,f][ 1,4]oxazepine-10-carbonyl)hydrazine.

3. As in claim 1, the compound which is1-(4-carboxybutyryl)-2-(8-chloro10,1 1 -dihydrodibenz[ b,f][1,4]oxazepine- 1 O-carbonyl )hydrazine.

4. As in claim 1, the compound which isl-(3-carboxypropionyl)-2-(8-ch1oro-10,1 1 -dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine.

5. As in claim 1, the compound which is l-phenoxyacetyl-2-(8-chloro-10,11 -dihydrodibenz[b,f][ 1,4]oxazepine-10-carbonyl)hydrazine. 6. As inclaim 1, the compound which is l-(p-chlorophenoxyacetyl)-2-(8-chloro10,1l-dihydrodibenz[b,f] 1 ,4 ]oxazepine- 10-carbonyl )hydrazine.

7. As in claim 1, the compound which is 1-(5-chloropentanoyl)-2-(8-chloro-10, 1 l-dihydrodibenz[b,f][ 1,4]oxazepinel0-carbony1)hydrazine.

8. As in claim 1, the compound which is 1-(5- chloropentanoyl )-2-(8-trifluoromethy1- 10, 1 l-dihydrodibenz[b,f][ 1,4]oxazepine-10-carbonyl)hydrazine.

9. As in claim 1, the compound which is l-cyanoacetyl-2-(8-chloro-10,1l-dihydrodibenz[b,f][ 1 ,4]oxazepine-10-carbony1)hydrazine.

10. As in claim 1, the compound which is 1-tri-

1. A COMPOUND OF THE FORMULA
 2. As in claim 1, the compound which is1-(3-carboxypropenoyl)-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.3. As in claim 1, the compound which is1-(4-carboxybutyryl)-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.
 4. As in claim 1, the compound which is1-(3-carboxypropionyl)-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.5. As in claim 1, the compound which is1-phenoxyacetyl-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.
 6. As in claim 1, the compound which is1-(p-chlorophenoxyacetyl)-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.
 7. As in claim 1, the compound whichis1-(5-chloropentanoyl)-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.
 8. As in claim 1, the compound which is1-(5-chloropentanoyl)-2-(8-trifluoromethyl-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.
 9. As in claim1, the compound which is1-cyanoacetyl-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.
 10. As in claim 1, the compound which is1-trifluoroacetyl-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl)hydrazine.